Method of providing an antihistaminic effect in a hepatically impaired patient

ABSTRACT

The present invention relates to a method of providing an antihistaminic effect in a hepatically impaired patient in need thereof comprising administering to said patient an effective antihistaminic amount of a compound of the formula  
                 
 
     wherein  
     R 1  is hydrogen or hydroxy;  
     R 2  is hydrogen;  
     or R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
     n is an integer of from 1 to 5;  
     R 3  is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;  
     each of A and B is hydrogen or hydroxy with the proviso that at least one of A or B is hydrogen;  
     or a pharmaceutically acceptable salt and individual isomers thereof.

[0001] This application is a continuation-in-part of application Ser.No. 07/880,801, filed May 11, 1992.

[0002] Terfenadine,α-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol,is a known antihistaminic agent which is currently availablecommercially under the name Seldane® with a recommended dosage of 60 mgB.I.D. (See PHYSICIAN'S DESK REFERENCE, 46th Edition, 1992, pp. 1349-50,Medical Economics Data, a division of Medical Economics Company, Inc.,Montvale, N.J. Terfenadine is disclosed in the Carr et al. '217 patent[U.S. Pat. No. 3,878,217, issued Apr. 15, 1975].

[0003] Terfenadine undergoes extensive (99%) first pass metabolism totwo primary metabolites, an active acid metabolite and an inactivedealkylated metabolite. The active acid metabolite has been identifiedas4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-benzeneaceticacid. The acid metabolite has been disclosed in the Carr et al. '129patent [U.S. Pat. No. 4,254,129, issued Mar. 3, 1981] as anantihistaminic agent having oral activity. Studies investigating theeffect of hepatic and renal insufficiency on the metabolism andexcretion of terfenadine are incomplete.

[0004] Preliminary information indicates that in cases of hepaticimpairment, significant concentrations of unchanged terfenadine can bedetected with the rate of acid metabolite formation being decreased. Insubjects with normal hepatic function, unchanged terfenadine plasmaconcentrations have not been detected.

[0005] Recently, it has been found that patients with impaired hepaticfunction (alcohol cirrhosis, hepatitis), or on ketokonazole ortroleandomycin therapy, or having conditions leading to QT prolongation(e.g., hypokalemia, congenital QT syndrome), may experience cardiacevents of QT prolongation and/or ventricular tachycardia at therecommended dose of terfenadine.

[0006] Surprisingly, it appears that patients with impaired hepaticfunction who are receiving terfenadine acid metabolite in sufficientamount so as to provide an antihistaminic effect will not experiencecardiac events of QT prolongation and/or ventricular tachycardia.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a method of providing anantihistaminic effect in a hepatically impaired patient in need thereofcomprising administering to said patient an effective antihistaminicamount of a compound of Formula (1)

[0008] wherein

[0009] R₁ is hydrogen or hydroxy;

[0010] R₂ is hydrogen;

[0011] or R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0012] n is an integer of from 1 to 5;

[0013] R₃ is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and is straight or branched;

[0014] each of A and B is hydrogen or hydroxy with the proviso that atleast one of A or B is hydrogen;

[0015] or a pharmaceutically acceptable salt and individual isomersthereof.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Compounds of Formula (1), and, in particular,4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-benzeneaceticacid, are prepared and used as described in Carr et al. [U.S. Pat. No.4,254,129, issued Mar. 3, 1981] which is hereby incorporated herein byreference in its entirety.

[0017] The present invention relates to a method of providing anantihistaminic effect in a hepatically impaired patient in need thereofcomprising administering to said patient an effective antihistaminicamount of a compound of Formula (1).

[0018] The compounds of Formula (1) are known histamine H₁-receptorantagonists and as such provide relief of symptoms associated withhistamine-mediated diseases and conditions such as seasonal allergicrhinitis, urticaria and the like.

[0019] As used herein, the term “patient” refers to a warm-bloodedanimal, such as a mammal, which is afflicted with a histamine-mediateddisease or condition. It is understood that dogs, cats, rats, mice, andhumans are examples of animals within the scope of the meaning of theterm.

[0020] A hepatically impaired patient is a patient having impaired liverfunction due to disease, such as alcoholic cirrhosis or hepatitis, ordue to administration of a drug, such as ketokonazole, erythromycin ortroleandomycin, which inhibits normal liver metabolic function. In thehepatically impaired patient, terfenadine is not metabolized at thenormal rate to the terfenadine acid metabolite.

[0021] When administered terfenadine at the recommended dosage, ahepatically impaired patient will experience increased levels ofterfenadine in the blood and decreased levels of the acid metaboliteover that expected with the non-hepatically impaired patient. Increasedblood levels of terfenadine in turn may cause decreases in the actionpotential and in various membrane currents of cardiac cells which maytrigger cardiac events of QT prolongation and/or ventriculartachycardia. Surprisingly, similar blood levels of the terfenadine acidmetabolite do not cause these decreases in the action potential and invarious membrane currents of cardiac cells. Therefore, at the same bloodlevels where terfenadine may trigger cardiac events of QT prolongationand/or ventricular tachycardia, the terfenadine acid metabolite will nottrigger these cardiac events.

[0022] The identification of those patients who may benefit from thepresent invention is well within the ability and knowledge of oneskilled in the art. A clinician skilled in the art can readily identify,by the use of clinical tests, physical examination and medical/familyhistory, those patients who are hepatically impaired and who are in needof treatment with an antihistamine.

[0023] An effective antihistaminic amount of a compound of Formula (I)is an amount which is effective in antagonizing the histamineH₁-receptor in a patient in need thereof which results in anantihistaminic effect.

[0024] An effective dose can be readily determined by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the effective dose, a number offactors are considered including,. but not limited to: the species ofpatient; its size, age, and general health; the specific diseaseinvolved; the degree of or involvement or the severity of the disease;the response of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; and the use of concomitant medication.

[0025] An effective antihistaminic amount of a compound of Formula (I)will generally vary from about 0.01 milligram per kilogram of bodyweight per day (mg/kg/day) to about 20 mg/kg/day, and will preferably bein the range of about 0.1 to about 6 mg/kg/day. A dose of about 10 mg toabout 200 mg two to four times per day is preferred. A dose of about 20mg to about 180 mg twice per day, or a single daily dose of about 40 mgto about 360 mg, are most preferred.

[0026] A compound of Formula (1) can be administered to a patient in anyform or mode which makes the compound bioavailable in effective amounts,including oral and parenteral routes. For example, compounds of Formula(1) can be administered orally, subcutaneously, intramuscularly,intravenously, transdermally, intranasally, rectally, and the like. Oraladministration is generally preferred. One skilled in the art ofpreparing formulations can readily select the proper form and mode ofadministration depending upon the particular characteristics of thecompound selected the disease state to be treated, the stage of thedisease, and other relevant circumstances.

[0027] The compounds can be administered alone or in the form of apharmaceutical composition in combination with pharmaceuticallyacceptable carriers or excipients, the proportion and nature of whichare determined by the solubility and chemical properties of the compoundselected, the chosen route of administration, and standardpharmaceutical practice. The compounds of the invention, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

[0028] The present invention contemplates compositions comprising acompound of Formula (1) in admixture or otherwise in association withone or more inert carriers. These compositions are useful, for example,as assay standards, as convenient means of making bulk shipments, or aspharmaceutical compositions. An assayable amount of a compound ofFormula (1) is an amount which is readily measurable by standard assayprocedures and techniques as are well known and appreciated by thoseskilled in the art. Assayable amounts of a compound of Formula (1) willgenerally vary from about 0.001% to about 75% of the composition byweight. Inert carriers can be any material which does not degrade orotherwise covalently react with a compound of Formula (1). Examples ofsuitable inert carriers are water; aqueous buffers, such as those whichare generally useful in High Performance Liquid Chromatography (HPLC)analysis; organic solvents, such as acetonitrile, ethyl acetate, hexaneand the like; and pharmaceutically acceptable carriers or excipients.

[0029] More particularly, the present invention contemplatespharmaceutical compositions comprising a therapeutically effectiveamount of a compound of Formula (1) in admixture or otherwise inassociation with one or more pharmaceutically acceptable carriers orexcipients.

[0030] The pharmaceutical compositions are prepared in a manner wellknown in the pharmaceutical art. The carrier or excipient may be asolid, semi-solid, or liquid material which can serve as a vehicle ormedium for the active ingredient. Suitable carriers or excipients arewell known in the art. The pharmaceutical composition may be adapted fororal or parenteral use and may be administered to the patient in theform of tablets, capsules, suppositories, solution, suspensions, or thelike.

[0031] The compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe invention, the active ingredient, but may be varied depending uponthe particular form and may conveniently be between 4% to about 70% ofthe weight of the unit. The amount of the compound present incompositions is such that a suitable dosage will be obtained. Preferredcompositions and preparations according to the present invention areprepared so that an oral dosage unit form contains between 5.0-300milligrams of a compound of the invention.

[0032] The tablets, pills, capsules, troches and the like may alsocontain one or more of the following adjuvants: binders such asmicrocrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch or lactose, disintegrating agents such as alginic acid,Primogel™, corn starch and the like; lubricants such as magnesiumstearate or Sterotex™; glidants such as colloidal silicon dioxide; andsweetening agents such as sucrose or saccharin may be added or aflavoring agent such as peppermint, methyl salicylate or orangeflavoring. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such aspolyethylene glycol or a fatty oil. Other dosage unit forms may containother various materials which modify the physical form of the dosageunit, for example, as coatings. Thus, tablets or pills may be coatedwith sugar, shellac, or other enteric coating agents. A syrup maycontain, in addition to the present compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

[0033] For the purpose of parenteral therapeutic administration, thecompounds of the present invention may be incorporated into a solutionor suspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the inventive compound presentin such compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between5.0 to 300 milligrams of the compound of the invention.

[0034] The solutions or suspensions may also include the one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

What is claimed is:
 1. A method of providing an antihistaminic effect ina hepatically impaired patient in need thereof comprising administeringto said patient an effective antihistaminic amount of a compound of theformula

wherein R₁ is hydrogen or hydroxy; R₂ is hydrogen; or R₁ and R₂ takentogether form a second bond between the carbon atoms bearing R₁ and R₂;n is an integer of from 1 to 5; R₃ is —COOH or —COOalkyl wherein thealkyl moiety has from 1 to 6 carbon atoms and is straight or branched;each of A and B is hydrogen or hydroxy with the proviso that at leastone of A or B is hydrogen; or a pharmaceutically acceptable salt andindividual isomers thereof.
 2. A method of claim 1 wherein R₁ ishydroxy.
 3. A method of claim 2 wherein n is
 3. 4. A method of claim 3wherein A and B are both hydrogen.
 5. A method of claim 1 wherein thecompound is4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-benzeneaceticacid.
 6. A method of claim 1 wherein the compound is(R)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-benzeneaceticacid.
 7. A method of claim 1 wherein the compound is(S)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-benzeneaceticacid.